This is the second report for this project. The two main protocols for this project have been approved and are in recruitment and accrual stages now. We have begun to enroll a cohort of patients with severe atopic dermatitis (AD) alone, and those with AD in the context of immune deficiency-- a patient group whose comorbid immunodeficiency may help point towards the pathophysiology underlying the atopic dermatitis. We have also begun accruing patients with genetic disorders which include atopy as a part of the syndrome. Concurrently, we have begun to develop screening assays for a number of pathways predicted to be disrupted in atopic dermatitis. These include TCR signaling, TCR repertoire and STAT3 axis disruptions. We have been able to generate novel data using some of these tools on a number of patients enrolled in the protocols which we believe may begin to shed light on the pathogenesis of the atopic disease, and yield basic insights into human T-cell biology. We are now in the recruitment phase to begin to treat patients with severe refractory atopic dermatitis with Anakinra, the IL-1 receptor antagonist. Additionally, we have been able to study the role of STAT3 in lymphocyte homeostasis. STAT3 disruption leads to elevated IgE and atopic dermatitis in the Hyper-IgE syndrome (HIES). A patient with STAT3 mosaicism was identified in collaboration with Dr. Steve Holland's group in the Laboratory of Clinical Infectious Diseases, and by sorting lymphocyte populations and sequencing for the mutant we have been able to establish the relative contribution of the mutant allele to T- and B-cell intrinsic defects seen in HIES. These defects may have specific roles in the pathogenesis of the atopic aspect of HIES, and therefore have broader implications for atopic disease in general. Furthermore, we have also been able to demonstrate that a potential consequence of this defect is a markedly increased risk for herpes zoster in these patients. We are actively pursuing further mechanistic explanations, and plan to begin an immunization project to determine the efficacy of zoster immunization in this young cohort of patients who nonetheless develop shingles at a high rate.